Mary Beth F. Son and Jane W. Newburger
Pediatrics in Review 2013;34;151
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collagen vascular disorders
Mary Beth F. Son, MD,*
Jane W. Newburger, MD,
Drs Son and
disclosed no ﬁnancial
to this article. This
contain discussion of
1. Clinicians should not dismiss the diagnosis of Kawasaki disease (KD) in children with
symptoms commonly attributed to viral illness. For example, severe headache and
photophobia should signal the possibility of aseptic meningitis even in the presence of
KD. And, right upper quadrant pain may indicate hydrops of the gallbladder.
2. A challenging subset of patients who do not meet the classic case deﬁnition are said
to have incomplete KD. Patients who have incomplete KD are more likely to be infants
and older children and, as such, are also at higher risk for coronary artery lesions (CAL).
Of note, infants younger than 6 months of age are at high risk for development of CAL,
yet often have fewer clinical features to facilitate the diagnosis. For these reasons,
echocardiography is recommended for infants younger than age 6 months with fever of
unclear etiology persisting for 7 or more days and elevated inﬂammatory markers.
investigative use of
a commercial product/
After reading this article, readers should be able to:
Describe the clinical manifestations of Kawasaki disease.
Formulate a differential diagnosis for patients with suspected Kawasaki disease.
Describe the laboratory values typically seen in Kawasaki disease.
Discuss the role of echocardiography in the management of patients who have
Kawasaki disease and describe the cardiac complications of the disease.
5. Deﬁne primary treatment of Kawasaki disease with intravenous immunoglobulin and aspirin.
A 3-year-old previously healthy Hispanic girl is brought to her pediatrician’s ofﬁce with
a history of 6 days of fever. The fever has been present daily and has been unremitting,
despite administration of antipyretic medications. She has been irritable with decreased
appetite. Her mother noticed an erythematous, nonpruritic rash covering her torso 1 day
after fever onset. She has developed red eyes in the past 2 days. She has no siblings and
attends child care.
On examination, the girl is febrile to 38.9°C and tachycardic at 140 beats per minute.
Her blood pressure while crying is 110/60 mm Hg. Her
weight is 14.5 kg. She has conjunctival injection with limbal
sparing and without exudate. Her lips appear erythematous
and cracked, and her oropharynx is diffusely erythematous
AHA: American Heart Association
without exudate. She does not have signiﬁcant cervical chain
lymphadenopathy. A polymorphous maculopapular rash
CAL: coronary artery lesions
covers her torso and extremities. The dorsa of her hands
CRP: C-reactive protein
and feet appear swollen.
EBV: Epstein-Barr virus
She has a total white blood cell count of 15,600/mm3,
ESR: erythrocyte sedimentation rate
a hemoglobin level of 9.8 g/dL, and a platelet count of
IVIG: intravenous immunoglobulin
670,000/mm3. The differential count of the white blood
KD: Kawasaki disease
cells is 81% neutrophils and 14% lymphocytes. She has mild
LAD: left anterior descending artery
transaminitis with an alanine aminotransferase level of 68
RCA: right coronary artery
U/L; her aspartate aminotransferase level is normal. Her
*Department of Pediatrics, National University Hospital, Singapore.
Department of Cardiology, Children’s Hospital Boston, Boston, MA.
Pediatrics in Review Vol.34 No.4 April 2013 151
collagen vascular disorders kawasaki disease
C-reactive protein (CRP) level is 9.8 mg/dL and her
erythrocyte sedimentation rate (ESR) is 65 mm/hour.
There are 25 white cells per high-power ﬁeld on urinalysis.
Kawasaki disease (KD) is an acute febrile illness of childhood characterized by vasculitis of medium-sized,
extraparenchymal arteries, with a predilection for coronary arteries. KD is the leading cause of acquired heart
disease in developed countries, although rheumatic
heart disease continues to dominate in the developing
world. The natural history and treatment of KD are well
described, but its etiology remains obscure, hampering
efforts to identify a speciﬁc diagnostic test and targeted
In the absence of a speciﬁc diagnostic test, KD remains
a diagnosis based on clinical criteria. All signs and symptoms of KD resolve following the acute illness, but coronary artery lesions (CALs) develop in 3% to 5% of
children treated with intravenous immunoglobulin
(IVIG), and up to 25% of untreated children. Its prognosis is predicated entirely on the presence and severity of
CALs, which can range from mild dilation to giant
aneurysms (Fig 1). It is unclear if children who have
normal-appearing coronary arteries during the acute phase
of the disease will be at risk for endothelial dysfunction
and accelerated atherosclerosis later in the life.
Figure 1. Selective right coronary angiogram demonstrating
multiple aneurysms in a child who has KD.
152 Pediatrics in Review Vol.34 No.4 April 2013
KD was ﬁrst described in 1967 by a Japanese pediatrician,
Dr Tomisaku Kawasaki, as the mucocutaneous lymph
node syndrome. (1) At that time, the cardiac involvement
of KD was not apparent, nor was effective treatment described. Within a few years, autopsy cases of patients who
had KD demonstrated coronary artery aneurysms and
thrombosis, and the cardiac complications of KD became
evident. Since Dr Kawasaki’s initial report, KD has been
described in children around the world, and in virtually all
races; however, Japanese children are at the highest risk.
Since 1970, Japan has collected epidemiologic data
about KD nearly every 2 years via nationwide surveys. Interestingly, although the birth rate has declined, the
numbers of patients diagnosed with KD and the incidence rate in Japan have risen rapidly since the 1990s.
There have been three documented epidemics of KD
in Japan, in 1979, 1982, and 1986. In 2010, the incidence rate of KD in Japan was 239.6 per 100,000 children age 0 to 4 years, which exceeds the highest rate
during any of the epidemics and is the highest rate recorded. The reason for the linear increase in the incidence
rate of KD in Japan is unclear. Similar to prior surveys in
Japan, the most recent survey in 2009–2010 found that
the incidence rate was highest among children age 6 to
11 months and was higher in boys than in girls. As compared with a survey performed in 1999–2000, the proportion of children with coronary artery dilation and
aneurysms decreased from 6% to 3%; however, the incidence of giant aneurysms in patients who had KD did
not decrease concomitantly. Infants, particularly those
younger than 6 months, as well as children at least age
5 years had an increased relative risk of developing CAL.
In contrast to Japan, hospitalization rates associated with
KD in the United States have been relatively stable over the
past decade. The rate in 1997 was 17.5 per 100,000 children younger than age 5 years, and in 2006, 20.8 per
100,000 children younger than age 5 years. Most hospitalizations occurred in children younger than age 3 years.
Children of Asian/Paciﬁc Islander descent had the highest
hospitalization rate, demonstrating the likely role of genetics in the pathogenesis of KD. An underlying genetic predisposition is supported further by the ﬁndings that siblings
of children who have KD have a 10-fold increased risk for
the disease, and the parents of children who have KD in
Japan today are twice as likely, compared with other adults,
to have had KD when they were children.
Risk factors for poor coronary artery outcomes have
been studied in several populations. Demographic factors,
such as young age, particularly younger than 6 months and
collagen vascular disorders kawasaki disease
older than 9 years, male gender, Asian and Paciﬁc Islander
race, and Hispanic ethnicity have been associated with
poor clinical outcomes. Laboratory parameters, such as
neutrophilia, thrombocytopenia, hyponatremia, elevated
CRP, and transaminitis, have all been associated with poor
response to IVIG and the development of CAL. (2) Essentially, patients with evidence of signiﬁcant and widespread
inﬂammation are at the highest risk.
KD’s etiology remains unknown. Many aspects of KD
mimic infectious processes, such as toxin-mediated illnesses and viral illnesses. Seasonal peaks have occurred
in the United States and Japan, with increased incidence
in localized areas, suggesting a transmissible vector. Researchers have looked painstakingly and unsuccessfully
for an etiologic infectious agent, including Epstein-Barr
virus (EBV), adenovirus, human coronavirus, human bocavirus, Yersinia pseudotuberculosis, herpes viruses, and others.
Toxins, such as those produced by Staphylococcus aureus
and Streptococcus pyogenes, have been postulated as the
causative agents of KD because the rash can resemble an
erythroderma, similar to the toxic shock syndromes and
staphylococcal scalded skin syndrome. Additionally, the
efﬁcacy of treatment with IVIG could be explained by immunoglobulin binding of the toxins, although antigenindependent mechanisms have been postulated as well.
Toxins act as superantigens, which nonselectively activate
large numbers of T cells, leading to massive cytokine release
and inﬂammation. Studies looking at the role of superantigens in KD have been conﬂicting. Speciﬁcally, isolation of
superantigen-producing organisms, isolation of superantigen proteins, and the presence of an immunologic signature
of superantigen activity have varied across studies.
To date, no unique agent has been proven to cause
KD. An alternative hypothesis posits that many infectious
agents trigger a ﬁnal common pathway in genetically susceptible hosts, which is supported by the ﬁnding that
many patients diagnosed as having KD have documented
concomitant infections. The interplay of infection and
vascular inﬂammation has been described in other forms
of vasculitis, such as hepatitis B and polyarteritis nodosa,
hepatitis C and cryoglobulinemia, and Staphylococcus and
granulomatosis with polyangitis (Wegener’s). Therefore,
the hypothesis that infectious agents may trigger the inﬂammatory cascade in KD has face validity.
Both the innate and adaptive arms of the immune system have been evaluated in the pathogenesis of KD. The
innate immune system includes epithelial barriers and
phagocytic cells that provide protection against infection,
whereas the adaptive immune response is mediated by
antigen-speciﬁc lymphocytes stimulated by infectious
agents. There is evidence that the innate immune system
plays a signiﬁcant role in the pathogenesis of KD. One
study reported that neutrophils are important actors in
the initial attack on coronary artery walls. (3) In a murine
model of coronary arteritis induced by Lactobacillus casei
cell wall extract, Toll-like receptor 2 and its downstream
adaptor protein, MyD88, are required for the development of coronary artery lesions, establishing a role for
the innate immune system. (4) Two recent studies demonstrated increased expression levels of innate immunityassociated genes during the acute phase of KD. (5)(6)
T cells also play an important role in KD. CD8þ T
cells have been found in the coronary arteries from autopsy specimens. Studies of acute and subacute sera in patients who have KD showed a decrease in the population
of T regulatory cells in the acute phase, with normalization following treatment with IVIG, indicating that impaired immunoregulation has a possible role in the
development of KD.
Recent genome-wide association studies have described
functional single-nucleotide polymorphisms in the ITPKC
(inositol 1,4,5 triphosphate 3-kinase C) gene that are associated with increased risks for susceptibility to KD, more
severe coronary artery disease, and resistance to IVIG. (7)
ITPKC acts as a negative regulator of T-cell activation
through the calcineurin/NFAT signaling pathway, and
alterations in signaling may contribute to immune hyperreactivity in KD.
To date, the role of B cells in the pathogenesis of KD
has not been clearly elucidated. Immunoglobulin A
plasma cells have been found in lung tissue and coronary
arteries from fatal cases of KD, but the precise role of the
immunoglobulin A plasma cells remains to be determined. Furthermore, a recent study using the murine
model with Lactobacillus casei cell wall extract–induced
coronary arteritis indicated that B cells are not required
for development of CALs. (8)
Classic clinical criteria with supportive clinical and laboratory ﬁndings are listed in Table 1. (9) With the exception of fever, the features of KD can ﬂuctuate, and
a thorough medical history is required to determine their
presence during the period of illness. Children who have
at least 4 days of fever (3 days in expert hands) and 4 or 5
of the principal criteria meet the case deﬁnition of KD.
The case deﬁnition also includes children with fewer than
four criteria if they have coronary artery disease.
The hallmark of KD is fever, typically above 39°C,
which has abrupt onset and may not remit with antipyretic
Pediatrics in Review Vol.34 No.4 April 2013 153
collagen vascular disorders kawasaki disease
Clinical and Laboratory Features of
Epidemiologic case deﬁnition (classic clinical criteria)
• Fever of at least 5 days’ duration
• Presence of at least 4 of the following principal features:
B Changes in extremities
B Polymorphous exanthem
B Bilateral conjunctival injection
B Changes in lips and oral cavity
B Cervical lymphadenopathy
• Exclusion of other diseases with similar ﬁndings (Table 2)
Other clinical and laboratory ﬁndings
• Cardiovascular ﬁndings
B Congestive heart failure, myocarditis, pericarditis, or valvular regurgitation
B Coronary artery abnormalities
B Aneurysms of medium-sized noncoronary arteries
B Raynaud phenomenon
B Peripheral gangrene
• Musculoskeletal system
• Gastrointestinal tract
B Diarrhea, vomiting, abdominal pain
B Hepatic dysfunction
B Hydrops of the gallbladder
• Respiratory tract
B Pulmonary nodules and interstitial inﬁltrates
B Pleural effusion
• Central nervous system
B Extreme irritability
B Aseptic meningitis
B Peripheral facial nerve palsy
B Sensorineural hearing loss
• Genitourinary system
B Testicular swelling
• Other ﬁndings
B Erythema and induration at Bacille Calmette-Guerin site
B Anterior uveitis
B Desquamating rash in groin
• Laboratory ﬁndings in acute Kawasaki disease (KD)
B Neutrophilia with immature forms
B Elevated erythrocyte sedimentation rate
B Elevated C-reactive protein (CRP) level
B Elevated serum a1-antitrypsin level
B Abnormal plasma lipids
B Thrombocytosis after ﬁrst week of illness
B Sterile pyuria
B Elevated serum transaminases
B Pleocytosis of cerebrospinal ﬂuid
B Leukocytosis in synovial ﬂuid
Reprinted with permission from Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment,
and long-term management of Kawasaki disease: a statement for health professionals from the
Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease
in the Young, American Heart Association. Circulation. 2004;110(17):2751.
154 Pediatrics in Review Vol.34 No.4 April 2013
medications. In the absence of treatment, fever typically lasts 11 to 12
days, with rare cases of prolonged fever lasting more than 3 weeks. Although some children treated with
IVIG experience immediate improvement during the infusion,
others defervesce 1 to 2 days after receiving IVIG. Approximately 15% of
children treated with IVIG have persistent or recrudescent fever more
than 36 hours after completion of
the ﬁrst IVIG infusion.
More than 90% of children who
have KD develop bilateral, nonexudative conjunctivitis that spares the limbus (ie, with clearing around the iris
(Fig 2). Anterior uveitis also may be
detected on slit-lamp examination during the acute phase of the disease.
Oropharyngeal manifestations are
common and include a diffusely erythematous oropharynx, red ﬁssured
lips, and a strawberry tongue (Fig 3).
Discrete oral ulcers and tonsillar exudates are not seen typically in KD.
KD rash usually appears within 5
days of fever onset, and often starts
as desquamation in the perineal area
that evolves into a diffuse, erythematous, maculopapular rash. Morbilliform rashes, erythema multiforma,
and erythroderma also can occur.
Bullous or vesicular lesions suggest
an alternative diagnosis.
Children afﬂicted with KD develop ﬁrm swelling of the hands
and feet, as well as erythema of
the palms and soles in the acute
phase of the disease. Characteristic,
although not pathognomonic, periungual peeling from the ﬁngers and
the toes (Fig 4) begins 2 to 3 weeks
after the onset of the fever.
Cervical lymph node enlargement is the least common criterion
found in patients who have KD.
The enlargement is usually unilateral, located in the anterior cervical
chain, nonﬂuctuant, and nontender.
The diameter of the involved node
collagen vascular disorders kawasaki disease
Figure 2. Bilateral nonexudative limbal sparing conjunctivitis
is found in up to 90% of children who have KD. Courtesy of
Annette L. Baker, NP.
should be ‡1.5 cm. Imaging typically reveals a group of
matted nodes without abscess formation.
Children who have KD can have a myriad of other signs
and symptoms, including myalgias, arthralgias, and arthritis. Neurologic involvement can include signiﬁcant
irritability, likely because of meningeal inﬂammation, transient facial palsies, and sensorineural hearing loss. Gastrointestinal complaints occur in up to 30% of patients and
include abdominal pain, vomiting, diarrhea, acalculous
distention of the gallbladder (hydrops), and hepatomegaly. Rarely, hemophagocytic lymphohistiocytosis, a lifethreatening complication in which activated macrophages
and T cells cause a cytokine storm, can occur in KD.
Figure 3. Oropharyngeal changes, including a strawberry
tongue, as pictured, are common in children who have KD.
Courtesy of Annette L. Baker, NP.
A challenging subset of patients who do not meet the
classic case deﬁnition are said to have incomplete or atypical KD. Children who have incomplete KD do not have
atypical features; rather, they have some of the classic features of KD but not enough to meet the case deﬁnition.
Patients who have incomplete KD are more likely to be
infants and older children, and, as such, also are at higher
risk for CALs.
Considering the cardiac consequences of failing to
treat incomplete KD and the comparative safety of IVIG
treatment, the American Heart Association (AHA) published an algorithm for the evaluation and treatment of
suspected incomplete KD to assist clinicians (Fig 5).
The algorithm uses laboratory values and echocardiography in those children who have only a few clinical features
of the disease, and also recommends consultation with
a KD expert if needed.
A multicenter retrospective study of patients who
have KD with aneurysms presenting before day 21 of
illness found that application of the AHA algorithm
would have resulted in referral of 97% of patients for
IVIG treatment. (10) Of note, infants younger than
age 6 months are at high risk for development of CALs,
yet often have few clinical features to facilitate the diagnosis. For these reasons, it is recommended that infants
younger than age 6 months who have had ‡7 days of
fever of unclear etiology and elevated inﬂammatory
markers undergo echocardiography.
Because KD is a self-limited febrile illness, infections
dominate the list of differential diagnoses (Table 2). Measles, adenovirus, enterovirus, and EBV can mimic the clinical presentation of KD. Measles does not occur typically in
countries with widespread vaccination; a travel or contact
history should be sought in cases in which coryza and
cough are conspicuous. Children who have adenoviral
or enteroviral illnesses typically are less ill compared with
children who have KD, and laboratory studies show less
evidence of inﬂammation, with lower white blood cell
counts and inﬂammatory markers. White blood cell indices
typically reveal lymphocytosis.
EBV is associated commonly with an exudative pharyngitis and diffuse lymphadenopathy, neither of which is seen
typically in KD. The conjunctivitis and rash of KD can be
quite prominent and may appear consistent with StevensJohnson syndrome. The absence of other clinical features
of KD, or ﬁndings of skin pain, skin necrosis, or blisters,
favors the diagnosis of Stevens-Johnson syndrome.
Pediatrics in Review Vol.34 No.4 April 2013 155
collagen vascular disorders kawasaki disease
Evaluation for Suspected KD
Figure 4. Periungual peeling, ﬁrst from the ﬁnger nailbeds and
then the toes, is typically seen 2 to 3 weeks after onset of the
fever. Courtesy of Annette L. Baker, NP.
Toxin-mediated syndromes triggered by staphylococcal or streptococcal infections usually are characterized by
visceral organ involvement, including renal insufﬁciency
and signiﬁcant hepatic dysfunction that are quite unusual
in KD. Hypotension is also quite prominent in the toxinmediated illnesses.
Scarlet fever can be evaluated with rapid streptococcal
antigen testing; fever caused by group A Streptococcus is
usually not associated with conjunctivitis and usually improves signiﬁcantly within 24 hours of initiation of antibiotics. Rocky Mountain spotted fever presenting with
fever and rash can appear similar to KD and occurs in speciﬁc geographic regions in the United States; treatment
for this potentially fatal infection should not be withheld
while KD is being considered.
Acrodynia can cause irritability and extremity changes
similar to KD; an ingestion history of mercury should be
sought if these are prominent manifestations. Children
who have systemic-onset juvenile idiopathic arthritis present with fever and rash, and coronary dilation on echocardiography has been described in this population; however,
the ocular and oropharyngeal signs of KD are quite unusual in the systemic form of arthritis.
Concomitant infections do not preclude the diagnosis
of KD. In one study from Toronto, over 30% of children
who had typical KD had laboratory evidence of at least
one infection. (11) Patients who have KD have nonspeciﬁc symptoms as well, such as headache, abdominal pain,
and malaise. Clinicians should not dismiss the diagnosis
of KD in children who have symptoms that are attributed
commonly to viral illnesses.
156 Pediatrics in Review Vol.34 No.4 April 2013
Children who have KD typically have leukocytosis with
a predominance of neutrophils and immature forms.
Many of these children have a normocytic normochromic anemia, with the average hematocrit at presentation
being 2 SDs below the norm for age. A sudden drop in
hemoglobin concentration following IVIG may be attributable to hemolytic anemia.
Platelet counts usually are elevated by the end of the
ﬁrst week of illness (450,000/mm3), and may evolve into
signiﬁcant thrombocytosis, with platelet counts averaging
700,000/mm3 by the third week. Platelet counts exceeding 1 million/mm3 are not uncommon. Relatively lower
platelet counts at the time of presentation are a risk factor
for later development of CAL, likely reﬂecting greater adherence of platelets to an activated endothelium. Rarely,
marked thrombocytopenia at diagnosis may be attributable to diffuse intravascular coagulation.
Inﬂammatory markers are elevated in nearly all cases
of KD. The ESR and CRP should be assessed at diagnosis. The ESR following treatment with IVIG often is
high, because the protein load from the infusion elevates
the ESR, obscuring the extent of disease activity. Nonetheless, measurements of the ESR can be helpful in assessing the degree of inﬂammation at diagnosis. CRP
levels are unaffected by IVIG and can be used in both
the acute and subacute phases to gauge the degree of
Transaminases are elevated in approximately 40% of
patients with KD, and a mild hyperbilirubinemia can occur. Plasma gammaglutamyl transpeptidase levels are elevated in approximately two thirds of patients who have
KD. Sterile pyuria (ie, dipstick negative) of ‡12 white
blood cells/mL is present in approximately 80% of
patients who have KD. Such pyuria may be found also
in children who have other febrile illnesses, but the magnitude is greater in patients who have KD. (12) Other
laboratory ﬁndings, such as hypoalbuminemia and hyponatremia, reﬂect more severe illness and can be associated with capillary leak. Lipid panels in patients who
have KD are markedly altered, with decreased levels
of total cholesterol, as well as apolipoprotein A1 and
high-density lipoprotein. Markers of cardiac damage
or dysfunction, such as troponins and B-type natriuretic
peptide, also may be elevated, but are not obtained
Although laboratory studies are not a component of
the classic criteria for KD, they are included in the algorithm for treatment of suspected incomplete KD, because
collagen vascular disorders kawasaki disease
Figure 5. Evaluation of suspected incomplete Kawasaki disease (KD). (1) In the absence of gold standard for diagnosis, this algorithm
cannot be evidence-based but rather represents the informed opinion of the expert committee. Consultation with an expert should be
sought any time assistance is needed. (2) Infants £6 months old on day ‡7 of fever without other explanation should undergo
laboratory testing and, if evidence of systemic inﬂammation is found, echocardiography, even if the infants have no clinical criteria. (3)
Patient characteristics suggesting KD are listed in Table 1. Characteristics suggesting disease other than KD include exudative
conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative
diagnoses (see Table 2). (4) Supplemental laboratory criteria include albumin £3.0 g/dL, anemia for age, elevation of alanine
aminotransferase, platelets after 7 days ‡450,000/mm3, white blood cell count ‡15,000/mm3, and urine ‡10 white blood cells/highpower ﬁeld. (5) Can treat before performing echocardiography. (6) Echocardiography is considered positive for purposes of this
algorithm if any of 3 conditions are met: z score of LAD or RCA ‡2.5, coronary arteries meet Japanese Ministry of Health criteria for
aneurysms, or ‡3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased left ventricular function,
mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2.0 to 2.5. (7) If echocardiography is positive, treatment should be
given to children within 10 days of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing
inﬂammation. (8) Typical peeling begins under nail bed of ﬁngers and then toes. Figure and legend reprinted with permission from
Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for
health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in
the Young, American Heart Association. Circulation. 2004;110(17):2748. CRP=C-reactive protein; echo=echocardiography;
ESR=erythrocyte sedimentation rate; f/u=follow-up; LAD=left anterior descending artery; RCA=right coronary artery.
Pediatrics in Review Vol.34 No.4 April 2013 157
collagen vascular disorders kawasaki disease
Differential Diagnosis of
B Epstein-Barr virus
B Scarlet fever
B Cervical lymphadenitis
B Rocky Mountain spotted fever
• Staphlycoccal scalded skin syndrome
• Toxic shock syndrome (associated with
Staphylococcus or Streptococcus)
• Drug hypersensitivity reactions
• Stevens-Johnson syndrome
• Systemic onset juvenile idiopathic arthritis
• Acrodynia (mercury toxicity)
many of the laboratory abnormalities described previously are seen consistently in KD.
The child has echocardiography performed. Her coronary artery dimensions are within normal limits for age,
but her left anterior descending artery does not taper normally. Her left ventricular function is normal, and no
pericardial effusion is seen.
Echocardiography is an excellent imaging modality for
evaluating coronary artery dimensions, myocardial function, valve regurgitation, and pericardial effusion. The procedure is noninvasive, and in experienced hands has high
sensitivity and speciﬁcity for dilation in the proximal coronary arteries. Sedation often is required in younger
children to obtain optimal images. If the diagnosis is
clear, treatment for KD should not be withheld while
waiting to schedule or obtain the results of echocardiography. Two-dimensional echocardiography should be
performed with the highest-frequency probe available
to produce high-resolution images. Standard views for
cardiac echocardiography include parasternal, apical, subcostal, and suprasternal notch windows.
Patients who have deﬁnite or suspected KD should undergo assessment of each coronary artery, including the
left main coronary artery, left anterior descending artery
(LAD), left circumﬂex coronary artery, right coronary
158 Pediatrics in Review Vol.34 No.4 April 2013
artery (RCA), and posterior descending coronary artery.
The proximal LAD and RCA are affected most commonly
by coronary artery aneurysms.
Coronary arteries should be evaluated with respect to
their size and appearance. The size of an artery should be
measured from internal edge to internal edge, avoiding
areas of branching that can be associated with areas of
natural dilation. The widely used Japanese Ministry of
Health criteria classify coronary artery sizes according
to age, with an internal lumen diameter greater than
3 mm abnormal in children less than age 5 years, and internal lumen diameter greater than 4 mm abnormal in
children age ‡5 years. Additionally, artery segments that
are ‡1.5 times larger than the adjacent section and those
segments having an irregular coronary lumen also are
considered abnormal. Because coronary artery dimensions change with the size of the child, body surface
area–adjusted coronary dimensions (z scores) also should
be obtained for the left main coronary artery, LAD, and
RCA. The other coronary arteries do not have established
z scores, and as such, the Japanese Ministry of Health criteria may be applied to those segments. Aneurysms can
be classiﬁed as small (<5 mm internal diameter), medium
(5–8 mm internal diameter), and giant (>8 mm internal
diameter) when using absolute dimensions.
The appearance of the coronary arteries is informative
as well. In most children who have KD, coronary diameters are greatest on the ﬁrst echocardiography performed
early in the disease. (13) Larger baseline measurements
predict the development of worsening CALs over the ensuing 4 to 6 weeks in a subset of children. If coronary artery dimensions are normal in the subacute period (up to
6 weeks), it is highly unlikely that the child will develop
dilatation of coronary vessels thereafter, unless the disease
relapses or recurs.
In addition to documenting ﬁndings in the coronary
arteries, echocardiography provides assessment of left
ventricular and valve function. Left ventricular systolic
dysfunction (ie, ejection fraction >2 SDs below normal)
occurs in 20% of children who have acute KD. Histologic
studies suggest that myocarditis is universal in patients who
have KD and can be severe enough to produce a clinical
picture consistent with shock. The myocarditis improves
rapidly with administration of IVIG. The pericardium
should be assessed with echocardiography for evidence
of effusion. Last, although mitral regurgitation is seen in
27% of patients early in the course of KD, aortic regurgitation is less common (1%).
Echocardiography should be obtained at diagnosis, 1
to 2 weeks later, and 6 weeks post discharge. Children
who have persistent or recrudescent fever or who have
collagen vascular disorders kawasaki disease
known CALs need more frequent monitoring to inform
treatment decisions, and close follow-up with a pediatric
cardiologist is essential. AHA recommendations suggest
follow-up echocardiography at 1 year in children who
never had coronary sequelae; however, echocardiography
should be performed more frequently among those who
Although echocardiography is the preferred method
of visualizing the coronary arteries early after KD, coronary angiography is used in children who have signiﬁcant
coronary artery aneurysms using techniques of computed
tomography, magnetic resonance angiography, or cardiac
Based on the clinical ﬁndings, the child is diagnosed as
having KD and is prescribed IVIG at 2 g/kg and aspirin
(ASA) 80 to 100 mg/kg per day divided every 6 hours.
Once the diagnosis of KD is conﬁrmed, treatment with highdose IVIG (2 g/kg) and high-dose ASA (80 to 100 mg/kg
per day divided into 4 doses) should be instituted promptly.
Ideally, treatment is administered within the ﬁrst 7 days of
illness, and by day 10 (as deﬁned by the ﬁrst day of fever)
at the latest. Treatment with IVIG after day 10 of illness
is reserved for those with ongoing fever and evidence of systemic inﬂammation on laboratory studies. To avoid infusion
reactions, premedication with standard dosing of diphenhydramine should be considered strongly. Additionally, IVIG
should be administered slowly, over 8 to 12 hours, to avoid
hemodynamic instability. IVIG can be associated with lowgrade fevers within the ﬁrst 48 hours of its administration.
Hemolytic reactions to IVIG are well described.
Approximately 15% of children who have KD will have
recurrent or persistent fever after the ﬁrst dose of IVIG
and are considered resistant to IVIG and at higher risk
for CALs. The treatment of these children remains an
area of controversy, because studies to evaluate treatment
strategies for IVIG resistance are limited. Most clinicians
administer another dose of IVIG (2 g/kg) 48 hours after
the ﬁrst dose if fever persists or is recrudescent.
Because KD is a vasculitis, corticosteroids have undergone
trials in KD. Steroids can be administered as “primary” therapy when given at the time of the ﬁrst dose of IVIG, or as
“secondary” therapy when given for IVIG resistance. Furthermore, corticosteroids can be given in high-“pulse” doses
of 30 mg/kg of intravenous methylprednisolone, or in lower
doses (0.5 to 2.0 mg/kg per day) of prednisolone orally.
The use of corticosteroids in KD has an interesting history, because an early report raised the possibility of
steroids worsening coronary artery disease; however,
subsequent studies indicated a likely beneﬁcial effect in
children. Most recently, a study by Kobayashi et al (14)
involving high-risk Japanese children showed that primary
therapy with a combination of corticosteroids (prednisolone 2 mg/kg per day) and IVIG provided protection
against poor coronary outcomes. However, this regimen
has not been tested in non-Japanese populations, and
the protocol involved a prolonged course of intravenous
corticosteroid with concomitant hospitalization. The optimal regimen of corticosteroids for IVIG resistance has yet
to be determined, and the lack of consensus has fostered
considerable practice variation across centers.
Other therapies used in IVIG resistance include inﬂiximab, a tumor necrosis factor inhibitor (5 mg/kg per
dose). Retrospective data indicate that inﬂiximab may decrease the number of days of fever, but may not alter coronary artery outcomes. Results of a prospective trial using
inﬂiximab as primary therapy are awaited. There are reports from Japan and the United States that calcineurin
inhibitors, such as cyclosporine A, may be effective in patients with IVIG resistance.
There are very few indications for ASA in childhood
given the risk of Reye syndrome, but KD remains one
of them. Studies have shown that use of ASA does not
affect the development of CALs (15); however, all of
the major clinical trials to study treatment of KD have
used ASA. Use of other nonsteroidal anti-inﬂammatory
drugs, such as ibuprofen, has not been studied recently.
In treating KD, ASA is given at high (anti-inﬂammatory)
doses of 80 to 100 mg/kg per day, divided into every-6hour dosing initially, followed by antithrombotic doses of
3 to 5 mg/kg per day in once-daily dosing.
There is practice variation in duration of high-dose
ASA administration. Some practitioners give high-dose
ASA until patients are afebrile for 48 hours, whereas
others continue with high-dose ASA for 2 weeks. Lowdose ASA typically is discontinued if echocardiography
ﬁndings are normal at the 6-week visit.
Children who have persistent CAL at 6 weeks are continued on low-dose ASA, and yearly inﬂuenza vaccinations
are strongly recommended in those cases to decrease the
risk of Reye syndrome. Patients who are not fully vaccinated
should receive immunizations according to the guidelines
put forth in the American Academy of Pediatrics’ Red Book,
which state that measles and varicella-containing vaccinations are contraindicated for 11 months after administration
of IVIG for KD. (16)
For those patients who have moderate to large aneurysms, a second antiplatelet agent may be added to ASA.
Children who have giant aneurysms require anticoagulation with low-molecular-weight heparin or warfarin, in
addition to ASA. Such regimens are best implemented
Pediatrics in Review Vol.34 No.4 April 2013 159
collagen vascular disorders kawasaki disease
with the collaboration of pediatric hematologists or coagulation services.
The role of 3-hydroxy-3-methylglutaryl coenzyme
A reductase inhibitors (statins) in children who have
KD remains an area of research. Statins have both
cholesterol-lowering and immunomodulatory properties.
In a small study of 11 children who had KD and CALs,
use of a statin for 3 months resulted in improved ﬂowmediated dilation (an indication of endothelial health)
and CRP levels. (17) Although these results are of interest, larger-scale clinical trials are needed before one can
recommend use of statins in the earliest phases of KD.
However, the threshold for use of statins in children
who have aneurysms is lower because of data suggesting
susceptibility of these patients to atherosclerosis.
The patient tolerates her IVIG infusion without complication and defervesces within the subsequent 48 hours. Her
tachycardia resolves. The conjunctival injection improves
signiﬁcantly, as does the rash. Upon discharge, she is well
appearing and prescribed ASA 40.5 mg daily. She is scheduled for an appointment in 2 weeks for echocardiography
and laboratory studies.
Prognosis and Long-Term Management
The prognosis of KD relates entirely to the extent and
severity of cardiac disease. With timely IVIG treatment,
the incidence of CAL in treated children has fallen to
less than 5%, and only 1% of children develop giant aneurysms. Coronary aneurysms regress to normal lumen diameter via proliferation of myoﬁbroblasts in more than one
half of affected arterial segments. However, endothelial
function is impaired in these segments even after regression. Stenoses at the proximal and distal ends of aneurysms
can develop over time and increase the risk of myocardial
ischemia. Stenotic lesions are more likely to form in giant
aneurysms, as compared with smaller lesions.
Management of children who have signiﬁcant coronary
artery disease may require a combination of beta-blockers
to decrease oxidative stress, as well as anticoagulation
therapy. These children are followed closely with assessment of coronary function (eg, exercise stress echocardiography in children old enough to run on a treadmill,
dobutamine cardiac magnetic resonance imaging for
younger children) and structure (echocardiography, coronary angiography).
In those who develop symptoms of angina or ﬁndings
of reversible ischemia on stress testing, percutaneous coronary intervention, for example with coronary stents, and
coronary artery bypass surgery may be indicated. A recent
report from Japan that followed patients who had giant
aneurysms into adulthood found that long-term survival is
160 Pediatrics in Review Vol.34 No.4 April 2013
relatively good among patients with giant aneurysms, despite
their need for multiple catheterizations and surgeries. (18)
Mortality from KD is low (<0.5%), with the highest
risk occurring in the ﬁrst year after illness onset because of acute myocardial infarction among patients
who have giant aneurysms. Sluggish blood ﬂow through
a dilated arterial segment and activation of platelets and
endothelium contribute to the risk for myocardial infarction. Children who have myocardial infarction may present with pallor, vomiting, and abdominal pain; older
children may complain of chest pain. Rupture of coronary
artery aneurysms is very rare, and generally occurs within
the ﬁrst few months of illness. Severe myocarditis leading
to hemodynamic compromise or arrhythmias can lead to
death in the ﬁrst week of illness.
Fortunately, most children who have KD do well after
a single dose of IVIG, with rapid clinical improvement
and reassuring echocardiographic ﬁndings. The risk of premature atherosclerosis among patients with always-normal
coronary arteries will not be known deﬁnitively until large
cohorts of middle-aged patients who have KD are assembled. In the interim, all children with a history of KD, even
those without apparent coronary artery involvement,
should undergo assessment of risk factors, such as hyperlipidemia and hypertension, and be counseled regarding
a healthy lifestyle and avoidance of modiﬁable cardiac risk
factors, such as obesity, smoking, and a sedentary lifestyle.
• Patients who have acute Kawasaki disease (KD) should
be treated promptly with intravenous immunoglobulin
(IVIG) to prevent coronary artery abnormalities (based
on strong research evidence). (19)
• Patients who have persistent or recrudescent fever
following primary therapy with IVIG should receive
another dose of IVIG at 2 g/kg (based primarily on
consensus). (9) Other secondary therapies to consider
include corticosteroids (14)(20) and inﬂiximab (21)
(based on some research evidence).
• Echocardiography is an excellent modality for
assessing coronary artery changes in children who
have early KD (based primarily on consensus).
• In patients who have KD and always-normal coronary
arteries, preventive cardiology counseling and followup are recommended until further studies delineate the
long-term consequences on endothelial health (9)
(based on some research evidence as well as consensus).
• In patients who have KD and coronary aneurysms,
cardiologic follow-up is tailored to the degree of
coronary artery involvement and involves assessment
of coronary function and structure (based on strong
research evidence). (9)
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lymphoid involvement with speciﬁc desquamation of the ﬁngers
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2. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with
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4. Rosenkranz ME, Schulte DJ, Agle LM, et al. TLR2 and MyD88
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to Kawasaki disease: analysis of pattern recognition receptor genes.
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1. A 3-year-old boy has had an unremitting fever for 4 days. Which of the clinical ﬁndings below best supports
Kawasaki disease (KD) as the explanation for his fever?
Bilateral cervical lymph node enlargement
Bilateral nonexudative conjunctivitis
Periungual peeling of ﬁngers and toes
Vesicles on the palms and soles
2. You are aware that other conditions can cause a similar clinical pattern. In your evaluation of this child, which
of the following conditions is initially most likely to be confused with KD?
A. Adenoviral infection
B. Pauciarticular juvenile arthritis
D. Staphylococcal scarlet fever
3. You order laboratory tests to add further diagnostic insights. Which of the following ﬁndings strengthen your
impression that the child has KD?
Elevated erythrocyte sedimentation rate
4. A 3-year-old girl meets clinical criteria for KD. You realize that the greatest threat to her is coronary artery
disease. The best choice for initial imaging of the coronary arteries is
Magnetic resonance angiography
5. Although her echocardiography shows no coronary artery lesions, you realize that the girl is at risk for
developing coronary artery disease and requires preventive therapy. The treatment that lowers the incidence of
coronary artery disease in KD the most is high-dose
Intravenous immune globulin
162 Pediatrics in Review Vol.34 No.4 April 2013